Poor bioavailability of lipophilic compounds is a well-known problem, in particular in connection with per oral administration, wherein the compound is to be dissolved in the gastric fluid and/or intestinal fluid before being absorbed from the gastro-intestinal tract into the blood circulation. Thus, the rate-limiting step in the absorption of compounds from the gastro-intestinal tract is often the dissolution rate of the compound in water and other liquids, which are similar to the ones found in the gastro-intestinal tract.
Many attempts at increasing the solubility of a lipophilic compound have been suggested and used in the past years. Examples are attempts to increase the surface area of a compound, either by spraying the amorphous compound onto an inert carrier or by micronising the compound. Other attempts have been directed to inclusion complexes with cyclodextrins. A common feature of the conventional techniques is that the compound is in particulate form, eg. in amorphous form or in crystalline form. Both forms still require the initial step of dissolving the particulate compound before being capable of penetrating the mucosa of the gastro-intestinal tract.
Typical examples of pharmaceutical formulation techniques which result in particulate forms of lipophilic compounds in the final composition/dosage form rather than in molecularly dispersed lipophilic compounds are as follows:
EP 0474 098 relates to the formulation of solid compositions comprising a hardly soluble drug substance co-precipitated with a carrier comprising a water-soluble excipient (PVP) and a biodegradable excipient (polyactic acid). This formulation technique aims at solving the problem of providing controlled release formulations.
U.S. Pat. No. 4,639,370 relates to the formulation of powdery compositions comprising a poorly water-soluble drug in combination with a water insoluble carrier (cross-linked PVP). The compositions are prepared by grinding/milling the drug substance and the cross-linked PVP without dissolving the active drug.
WO 03/04360 relates to the formulation of solid dispersions comprising a poorly water-soluble drug in combination with a carrier (PVP). The compositions are prepared by dissolving the drug compound and the carrier (PVP) in a volatile solvent and then removing the solvent.
U.S. Pat. No. 6,027,747 relates to the formulation of solid compositions comprising a hardly soluble drug substance together with a carrier (PVP). The compositions are made by a process including dissolving the drug in a volatile organic solvent together with a hydrophilic polymer and evaporating the solvent to dryness to form a co-precipitate of the drug with the hydrophilic polymer.
Khougaz K et al. relates to the formulation of solid dispersions comprising a hardly soluble drug substance together with a carrier (PVP), wherein the drug substance is present in amorphous form or in crystalline form (Khougaz K et al. Crystallisation inhibition in solid dispersions of MK-0591 and PVP polymers, J Pharm Sci vol 89, October 2000, pages 1325-1334).
Watanabe T et al. relates to the formulation of solid compositions comprising indomethacin and silica. The indomethacin is physically mixed with the silica by co-grinding or melting resulting in amorphous form of indometacin (Watanabe T et al. Stability of amorphous indomethacin compounded with silica, Int J Pharm, 226, 2001, pages 81-91).
Watanabe T et al. also relates to the formulation of solid compositions comprising indomethacin and silica. The indomethacin is physically mixed with the silica by co-grinding or melting resulting in amorphous form of indometacin (Watanabe T et al. Prediction of apparent equilibrium solubility of indometacin compounded with silica by 13C solid state NMR′, Int J Pharm, 248, 2002, pages 123-129).
Watanabe T et al relates to the formulation of solid compositions comprising indomethacin and silica or PVP. The indomethacin is physically mixed with the silica or PVP by co-grinding or melting resulting in amorphous form of indometacin (Watanabe T et al. Comparision between Polyvinylpyrrolidone and silica nano particles as carriers for indomethacin in a solid state dispersion. Int J Pharm, 250, 2003, pages 283-286).
GB 1 365 661 relates to the formulation of solid compositions comprising a drug substance with low water solubility (Cholesteryl beta-glucoside) and a carrier (Silica (Aerosil™). The composition is prepared by dissolving the betaglucoside in hot ethanol and subsequently adding this solution to the aerosol powder and evaporate the solvent from the resulting slurry. The resulting composition has a slower release rate than conventional formulations.
Takeuchi et al relates to the formulation of compositions wherein the drug compound (tolbutamide) is present in amorphous form (Takeuchi et al. Spherical solid dispersion containing amorphous tolbutamide embedded in enteric coating polymers or colloidal silica prepared by spray-drying technique. Chem Pharm Bulletin Pharm Soc Japan. 35, 1987, pages 3800-3806).
Chowdary K et al. relates to the formulation of solid dispersions (powders) prepared by dissolving the drug (Meloxicam) in a solvent in the presence of carrier (Silica, Aerosil). The solvent is then evaporated to dryness. The process of evaporating the solvent to dryness will result in the drug precipitating onto the carrier (Chowdary K et al. Enhancement of dissolution rate of meloxicam. Indian J Pharm Sci, 63, 2001, pages 150-154).
Nakakami H relates to the formulation of solid dispersions comprising poorly water-soluble drugs and non-porous fumed silicon dioxide as the carrier (Nakakami H. Solid dispersions of indomethacin and griseofulvin in non-porous fumed silicon dioxide, prepared by melting. Chem Pharm Bulletin Pharm Sci Japan, 39, 1991, pages 2417-2421).
Monkhouse D C et al relates to the formulation of fine powders of a drug and a carrier (fumed silica). The drug and the silica are mechanically mixed under addition of an organic volatile solvent (acetone, chloroform or methylene chloride) in order to totally dissolve the drug in the sample. The solvent is then evaporated to dryness. As the solvent is evaporated to dryness the drug will precipitate onto the carrier (Monkhouse D C et al. Use of adsorbents in enhancement of drug dissolution I. J Pharm Sci, Am Pharm Ass Washington, 61, 1972, 1430-1435).
WO 01/52857 relates to the formulation of solid compositions comprising drospirenone and an estrogen, wherein the drospirenone is initially dissolved in a solvent and then sprayed onto the surface of an inert carrier.
Obviously, the administration of a compound that is in the dissolved stage already at the time of administration may be advantageous in terms of ensuring high bioavailability. For example, by dissolving a compound in a suitable oil or another lipophilic medium. Unfortunately, it is often found that the amount of drug which is dissolvable in the lipophilic media is too low, for which reason the oil cannot be administered in an acceptable form, such as enclosed in a capsule or the like.
Supersaturated solutions of lipophilic compounds are known approaches for making solutions containing lipophilic compounds in a dissolved stage. The concentration of a dissolved compound in a supersaturated solution is higher than the solubility of the compound in the actual solvent at room temperature. However, the physical stability of the compound in such a supersaturated solution is critical in that re-crystallisation of the compound occurs. Therefore, this technique cannot be applied as a general technique to lipophilic compounds as such.
Therefore, pharmaceutical dosage forms having the lipophilic drug in a readily dissolvable form and which are also physically stable (no tendency to crystallisation of the lipophilic drug) and which contain the lipophilic drug in a satisfactorily high concentration would solve the problems associated with other techniques.